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ALPRAZOLAM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Alprazolam is a triazolo analog of the 1,4-benzodiazepine class with similar properties as other benzodiazepines (ie, sedative/hypnotic and antianxiety properties), with its action on the central nervous system. These effects appear to be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid, with the opening of chloride channels.

Specific Substances

    1) U-31889
    2) 8-Chloro-1-methyl-6-phenyl-4H-1,2,4-triazolo(4,3- a)(1,4)benzodiazepine
    3) CAS 28981-97-7
    1.2.1) MOLECULAR FORMULA
    1) C17H13CIN4

Available Forms Sources

    A) FORMS
    1) Alprazolam is available as 0.25 mg, 0.5 mg, 1 mg, and 2 mg immediate-release tablets (Prod Info alprazolam oral tablets, 2007), 0.5 mg, 1 mg, 2 mg, and 3 mg extended-release tablets (Prod Info XANAX(R) XR extended-release oral tablets, 2005), 0.25 mg, 0.5 mg, 1 mg, and 2 mg orally disintegrating tablets (Prod Info NIRAVAM(TM) orally disintegrating tablets, 2005), and as a 1 mg/mL oral solution (Prod Info ALPRAZOLAM INTENSOL(TM) oral solution, 2007).
    B) USES
    1) Alprazolam is used as an antianxiety agent. It is also used for the treatment of panic disorder, with or without agoraphobia (Prod Info alprazolam oral tablets, 2007; Prod Info ALPRAZOLAM INTENSOL(TM) oral solution, 2007; Prod Info XANAX(R) XR extended-release oral tablets, 2005; Prod Info NIRAVAM(TM) orally disintegrating tablets, 2005).
    2) There is evidence to suggest that alprazolam, unlike other benzodiazepines, has some antidepressant activity (Feighner, 1982).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Used as an anti-anxiety agent and for the treatment of panic disorder, with or without agoraphobia.
    B) PHARMACOLOGY: Acts on the benzodiazepine binding site on the chloride channel of the gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter receptor in the CNS, and increases the frequency of chloride channel opening. This hyperpolarizes the cell and prevents nerve firing/stimulation, resulting in generalized depression of spinal reflexes and the reticular activating system causing CNS depression.
    C) TOXICOLOGY: Toxicity is an extension of the pharmacology, increased GABA activity causing CNS depression. While coma and respiratory depression are rare, they may occur with large overdoses or coingestions.
    D) EPIDEMIOLOGY: Overdose is common and usually occurs in combination with other drug ingestions. Outcomes are generally good.
    E) WITH THERAPEUTIC USE
    1) Adverse effects of alprazolam in therapeutic doses usually reflect the drug's pharmacology and include sedation, slurred speech, and ataxia. Tachycardia and hypotension may also occur during therapeutic use. Benzodiazepines may induce or worsen dyskinesia symptoms. Respiratory arrest has occurred following rapid IV administration of therapeutic doses of benzodiazepines.
    2) Physical and/or psychological dependence may develop, and a withdrawal syndrome similar to ethanol withdrawal (ie, hypertension, tachycardia, tremulousness, seizures, low grade fever, and, in severe cases, delirium) may develop after abrupt discontinuation in dependent individuals.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: CNS depression is the most common finding after overdose. Respiratory depression may also occur, but is more common with coingestion of other sedative-hypnotics. Ataxia, confusion, diminished reflexes, impaired coordination, lethargy, sleepiness, and slurred speech are common with overdose. Dilated pupils may be present in overdose.
    2) SEVERE TOXICITY: Respiratory depression/arrest may occur with large overdoses. Severity of respiratory effects depends on the amount ingested and absorbed and coingestants. Atrioventricular block has been reported following overdose. In high doses, patients may manifest coma and respiratory depression. Otherwise, alprazolam is remarkably safe as a single agent.
    0.2.20) REPRODUCTIVE
    A) Alprazolam is classified as FDA pregnancy category D. Generally, alprazolam should be avoided, at least during the first trimester and at delivery. Both animal data and human epidemiological studies suggest benzodiazepines are teratogens.

Laboratory Monitoring

    A) Monitoring vital signs, venous blood gases, ECG, and pulse oximetry may be useful.
    B) Qualitative testing for presence of alprazolam is helpful to confirm presence, especially when overdose history is sketchy; however, quantitative levels are not usually clinically useful.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUPPORT
    1) Supportive care with attention to the airway, breathing, and circulation is the mainstay of treatment. Overdose of a benzodiazepine as a single agent may cause coma but generally does not cause loss of airway reflexes. However, when combined with other sedating drugs (eg, ethanol, opioids, muscle relaxants, antipsychotics, anticonvulsants), airway protection may be necessary. Even with large overdoses, patients generally remain hemodynamically stable.
    B) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Supportive care.
    C) MANAGEMENT OF SEVERE TOXICITY
    1) Coma and respiratory depression require intubation. Hypotension responds to fluids and rarely vasopressors.
    D) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is usually not necessary unless the patient has a dangerous co-ingestant. Avoid if the patient is too sedated.
    2) HOSPITAL: Activated charcoal may be beneficial if dangerous co-ingestants were consumed and the patient is intubated or can protect their airway. Gastric lavage and whole bowel irrigation are usually not indicated as severe toxicity is very rare.
    E) AIRWAY MANAGEMENT
    1) Although respiratory depression is rare, some patients may require airway management.
    F) ANTIDOTE
    1) Flumazenil is a specific benzodiazepine receptor antagonist that can rapidly reverse the benzodiazepine effect. However, it is rarely indicated except for iatrogenic oversedation or respiratory depression. In addition, flumazenil may cause withdrawal states and result in seizures, adrenergic stimulation, or autonomic instability in patients chronically taking benzodiazepine, and may cause ventricular dysrhythmias and seizures in patients with concomitant cocaine or tricyclic antidepressant toxicity. The starting dose is 0.1 to 0.2 mg IV over 15 to 30 seconds and repeated as needed to a maximum of 1 mg. Continuous IV infusion from 0.1 to 1 mg/hr in 0.9% NaCl or D5W may also be used.
    G) ENHANCED ELIMINATION
    1) There is no role for diuresis, dialysis, or hemoperfusion.
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: Healthy children with unintentional ingestions of 0.5 mg or less may be observed at home if the family is responsible. If significant ataxia or drowsiness develops, refer the patient to the hospital. Asymptomatic adults with unintentional ingestions and a good social situation may remain at home.
    2) OBSERVATION CRITERIA: All patients with intentional ingestion or significant ataxia, drowsiness, or respiratory depression should be referred to the hospital for observation. Patients with unreliable social situations may also need observation. Patients may be discharged when asymptomatic.
    3) ADMISSION CRITERIA: Admit patients with severe symptoms (ie, coma, respiratory failure, or hypotension unresponsive to IV fluids) or if a danger to themselves. Discharge when asymptomatic and when psychiatric issues have been addressed.
    I) PITFALLS
    1) Profound coma, respiratory failure, and significant hemodynamic instability suggest a co-ingestant and indicate the need for further investigation. Indiscriminate flumazenil administration to comatose patients may cause seizures or dysrhythmias.
    J) PHARMACOKINETICS
    1) Alprazolam is readily absorbed, with peak plasma concentrations occurring within 1 to 2 hours following administration. It is 80% protein bound, primarily to albumin. Alprazolam is extensively metabolized, mostly via cytochrome P450 3A4 enzymes. Plasma elimination half-life is approximately 11 hours.
    K) PREDISPOSING CONDITIONS
    1) Benzodiazepines co-ingested with other sedating agents increase the risk for respiratory compromise. Obese patients have longer elimination half-lives and prolonged drug effect. Sleep apnea patients and those with other underlying chronic pulmonary diseases may be at increased risk for respiratory depression.
    L) DIFFERENTIAL DIAGNOSIS
    1) Various sedative-hypnotics, including ethanol, antidepressants, anticonvulsants, antipsychotics, barbiturates, and opioids, can cause sedation and minimal vital sign changes in overdose.

Range Of Toxicity

    A) TOXICITY: Deaths from benzodiazepine overdose are extremely rare. A patient with multiple severe medical problems expired following an overdose of 7.5 mg of alprazolam. In general, the toxic-to-therapeutic ratio is very high for benzodiazepines, making them remarkably safe medications.
    B) Ataxia, sleepiness, and slurred speech may be noted following ingestion of the first therapeutic dose of these agents, especially in children.
    C) THERAPEUTIC DOSE: ADULTS: As an anti-anxiety agent, the recommended dose is 0.25 to 0.5 mg given orally three times a day up to a maximum daily dose of 4 mg. For the treatment of panic disorder, the usual recommended dose ranges from 3 to 6 mg daily.

Clinical Effects

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Respirations are often decreased following benzodiazepine overdoses (Hojer et al, 1989).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) In a retrospective study of all patients admitted to a medical intensive care unit for benzodiazepine ingestion, 15% were hypothermic on admission (Hojer et al, 1989).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) In a retrospective study of all patients admitted to a medical intensive care unit for benzodiazepine ingestion, 10% were hypotensive on admission.
    a) Hypotension was noted less frequently in the subgroup of patients that did not ingest any other substance (Hojer et al, 1989).
    2) Cardiovascular effects are generally mild or absent. Changes suggest the presence of other agents.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) For pure toxic alprazolam ingestions, HEENT effects are minimal.
    2) MYDRIASIS may be present.
    3) NYSTAGMUS has been reported in patients following overdose of chlordiazepoxide and ethanol (Bailey, 1984).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia may be observed due to anticholinergic effects during therapeutic use (Prod Info alprazolam oral tablets, 2007).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) During a placebo-controlled trial, hypotension occurred in 4.7% of patients taking alprazolam (n=565) as compared to 2.2% of patients in the placebo group (n=505) (Prod Info alprazolam oral tablets, 2007).
    C) ATRIOVENTRICULAR BLOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 28-year-old male intentionally ingested 12 milligrams of alprazolam, reporting that his usual dose of 1-2 milligrams did not relieve his anxiety, and developed drowsiness along with marked first-degree atrioventricular block with a PR interval of 500 milliseconds (Mullins, 1999). AV block was effectively reversed with flumazenil (total dose 2.0 milligrams).
    1) The authors concluded that alprazolam may exert a direct effect on the AV nodal conduction velocity as observed by the rapid shortening of the PR interval; flumazenil did not affect atrial rate.
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CIRCULATORY FAILURE
    a) Massive intravenous doses (greater than 195 mg/kg which is equivalent to 975 times the maximum recommended daily human dose of 10 mg/day) of alprazolam in experimental laboratory animals have resulted in cardiopulmonary collapse (Prod Info alprazolam oral tablets, 2007).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression is the primary clinical effect to anticipate in alprazolam overdose. Severity will depend on amount ingested and amount absorbed (history of vomiting or treatment prior to arrival at ED).
    b) INCIDENCE: In a series of 131 patients with alprazolam overdose, 16% required intubation and mechanical ventilation (Isbister et al, 2004). This was more frequent than in the 823 patients with diazepam overdose (8%) and 1109 patients with overdose with other benzodiazepines (10.8%).
    c) INCIDENCE: 37% required orotracheal intubation and 18% required administration of artificial ventilation following an ingestion of a benzodiazepine alone in a retrospective study of all patients admitted to a medical intensive care unit for benzodiazepine ingestion (Hojer et al, 1989).
    B) APNEA
    1) WITH THERAPEUTIC USE
    a) Respiratory arrest has been reported following intravenous administration of therapeutic doses of benzodiazepines (Anon, 1986).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) Patients may demonstrate no more than sleepiness, stage 0 to 1 coma even following large overdoses. Ataxia, confusion, diminished reflexes, impaired coordination, lethargy, and slurred speech are common (Prod Info alprazolam oral tablets, 2007).
    1) Initial phases may produce minor extrapyramidal signs with some excitement.
    2) Coma unresponsive to stimulation such as sternal pressure is quite uncommon. Deep coma, marked hypotension, and respiratory depression may indicate other drugs have been ingested as well.
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) INCIDENCE: In a series of 131 alprazolam overdoses, 12.2% had a glasgow coma score of less than 9 (Isbister et al, 2004). This was slightly more than was reported in 823 patients with diazepam overdose (6.9%) or 1109 patients with overdose with other benzodiazepines (9.7%).
    b) In a retrospective study, 49% (71/144) of patients were in grade 3 or 4 coma on admission following benzodiazepine alone ingestions. There were 14 of 71 patients in coma for more than 24 hours and 5 were still comatose after 48 hours (Hojer et al, 1989).
    c) Alpha coma has been reported following an overdose of a benzodiazepine (Guterman et al, 1981). Alpha coma associated with drug toxicity is associated with a good prognosis, as compared to the grim prognosis observed with alpha coma following cerebral anoxic insults.
    C) DROWSY
    1) WITH THERAPEUTIC USE
    a) Degree of impairment and sedation related better to dose than blood concentration in a study of 3 different doses of alprazolam (0.25 mg every 8 hours, 0.5 mg every 8 hours, and 2 mg every 12 hours) in elderly patients (Kroboth et al, 1990).
    2) WITH POISONING/EXPOSURE
    a) Somnolence is one of the neurological effects associated with alprazolam overdose (Prod Info alprazolam oral tablets, 2007).
    D) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) It has been reported that the benzodiazepine agents may worsen or induce dyskinesia in susceptible personalities (Francis, 1983; Rosenbaum & De La Fuente, 1979).
    b) Oral dyskinesia associated with low dosage benzodiazepine treatment has been reported (Kaplan & Murkofsky, 1978).
    E) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) Dystonic reactions associated with acute benzodiazepine ingestions, other than alprazolam, have been reported (Hooker & Danzl, 1988).
    1) Resolution of the dystonia occurred following treatment with diphenhydramine 50 mg IV.
    b) This effect may be related to benzodiazepine facilitation of GABA activity, resulting in decreased dopaminergic activity, increased central cholinergic activity, and EPS.
    F) AGGRESSIVE BEHAVIOR
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Combativeness has been reported following ingestion of 60 mg alprazolam by a 29-year-old female (McCormick et al, 1985).
    G) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures have been reported in patients receiving benzodiazepines during withdrawal (Schneider et al, 1987).
    b) Grand mal seizures have been associated with discontinuation of alprazolam (Breier et al, 1984; Levy, 1984; Noyes et al, 1986). Myoclonic seizures have been reported following abrupt withdrawal from phenelzine and alprazolam (Naylor et al, 1987).
    c) Withdrawal symptomatology occurs within 72 hours of abstinence. Seizures were self-limiting and of short duration, and the total daily dose of alprazolam exceeded the manufacturer's recommended maximum daily dose of 4 mg for 8 weeks to 18 months in these cases (Browne & Hauge, 1986).
    H) AMNESIA
    1) WITH THERAPEUTIC USE
    a) In a test of learning performance consisting of the ability to recall 16 words, the alprazolam (9.8 +/- 1.2) group differed significantly from placebo (14.3 +/- 0.7) at 24 hours after a single oral dose (Greenblatt et al, 1988).
    I) DISTURBANCE IN SPEECH
    1) WITH POISONING/EXPOSURE
    a) Dysarthria has been reported following overdose (Bailey, 1984).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Alprazolam ingestions will produce minimal effects (nausea, vomiting, diarrhea, and constipation) on the GI tract during therapeutic use.
    2) WITH POISONING/EXPOSURE
    a) Bowel sounds may be absent following overdose, similar to other benzodiazepines.

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL SEXUAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Reversible sexual dysfunction has been reported in both male and females in doses ranging from 3 to 10 mg/day of alprazolam (Uhde et al, 1988; Sangal, 1985; Munjack & Crocker, 1986; Lydiard et al, 1987).
    1) Patients return to baseline when the dose of alprazolam is reduced.

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) Bullae have been reported in a comatose patient following a single overdose ingestion of a benzodiazepine (Ridley, 1971).

Reproductive

    3.20.1) SUMMARY
    A) Alprazolam is classified as FDA pregnancy category D. Generally, alprazolam should be avoided, at least during the first trimester and at delivery. Both animal data and human epidemiological studies suggest benzodiazepines are teratogens.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Severe dysmorphism, malformations, intrauterine and extrauterine growth restriction, and CNS dysfunction have been described in seven infants born of mothers who used benzodiazepines during pregnancy (Laegreid et al, 1987).
    B) LACK OF EFFECT
    1) Some reports have shown benzodiazepines to be free of teratogenic effects (Winter, 1987; Czeizel & Lendvay, 1987; Gerhardsson & Alfredsson, 1987).
    3.20.3) EFFECTS IN PREGNANCY
    A) CONGENITAL ANOMALY
    1) The controversy over prescribing benzodiazepines during pregnancy is discussed in an extensive review (Weber, 1985).
    a) Both animal data and human epidemiological studies suggest benzodiazepines are teratogens. Attack on the CNS by benzodiazepines can occur during organogenesis, during early differentiation of neural anlagen (hereditary factor) after neural tube dosing, or during biochemical differentiation of the brain.
    B) NEONATAL FLACCIDITY
    1) Neonatal flaccidity has been reported in children born to mothers exposed to benzodiazepines (Prod Info alprazolam oral tablets, 2014; Prod Info ALPRAZOLAM Intensol(TM) oral solution, 2014; Prod Info Xanax XR(R) oral extended-release tablets, 2013; Prod Info NIRAVAM(R) orally disintegrating tablets, 2013).
    C) RESPIRATORY PROBLEMS
    1) Respiratory problems have been reported in children born to mothers exposed to benzodiazepines (Prod Info alprazolam oral tablets, 2014; Prod Info ALPRAZOLAM Intensol(TM) oral solution, 2014; Prod Info Xanax XR(R) oral extended-release tablets, 2013; Prod Info NIRAVAM(R) orally disintegrating tablets, 2013).
    D) WITHDRAWAL SYNDROME
    1) Withdrawal symptoms may occur during the postnatal period in children born to mothers exposed to benzodiazepines (Prod Info alprazolam oral tablets, 2014; Prod Info ALPRAZOLAM Intensol(TM) oral solution, 2014; Prod Info Xanax XR(R) oral extended-release tablets, 2013; Prod Info NIRAVAM(R) orally disintegrating tablets, 2013).
    2) WITHDRAWAL SYMPTOMS and sedation have been noted in newborns after antepartum use of benzodiazepines in the mother (Anderson & Kelley-Buchanan, 1988), including alprazolam (Barry & St Clair, 1987).
    3) Investigations are currently underway to evaluate an intrauterine dependency and a low dose physical dependency (Smith & Wesson, 1983).
    E) PREGNANCY CATEGORY
    1) The manufacturer has classified alprazolam as FDA pregnancy category D (Prod Info alprazolam oral tablets, 2014; Prod Info ALPRAZOLAM Intensol(TM) oral solution, 2014; Prod Info Xanax XR(R) oral extended-release tablets, 2013; Prod Info NIRAVAM(R) orally disintegrating tablets, 2013).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Alprazolam is excreted into human breast milk (Briggs et al, 1998). Based on its potential effects on an infant's neurodevelopment, alprazolam should be avoided during lactation.
    2) Crying, irritability, and sleep disturbances were noted in an infant exposed to alprazolam via breast milk which were associated with maternal withdrawal from the medication over a three week period (Anderson & McGuire, 1989; Briggs et al, 1998).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: No impairment of fertility was observed in rats administered up to 5 mg/kg/day (25 times the maximum recommended human dose of 10 mg/day) (Prod Info alprazolam oral tablets, 2014; Prod Info ALPRAZOLAM Intensol(TM) oral solution, 2014; Prod Info Xanax XR(R) oral extended-release tablets, 2013).

Summary Of Exposure

    A) USES: Used as an anti-anxiety agent and for the treatment of panic disorder, with or without agoraphobia.
    B) PHARMACOLOGY: Acts on the benzodiazepine binding site on the chloride channel of the gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter receptor in the CNS, and increases the frequency of chloride channel opening. This hyperpolarizes the cell and prevents nerve firing/stimulation, resulting in generalized depression of spinal reflexes and the reticular activating system causing CNS depression.
    C) TOXICOLOGY: Toxicity is an extension of the pharmacology, increased GABA activity causing CNS depression. While coma and respiratory depression are rare, they may occur with large overdoses or coingestions.
    D) EPIDEMIOLOGY: Overdose is common and usually occurs in combination with other drug ingestions. Outcomes are generally good.
    E) WITH THERAPEUTIC USE
    1) Adverse effects of alprazolam in therapeutic doses usually reflect the drug's pharmacology and include sedation, slurred speech, and ataxia. Tachycardia and hypotension may also occur during therapeutic use. Benzodiazepines may induce or worsen dyskinesia symptoms. Respiratory arrest has occurred following rapid IV administration of therapeutic doses of benzodiazepines.
    2) Physical and/or psychological dependence may develop, and a withdrawal syndrome similar to ethanol withdrawal (ie, hypertension, tachycardia, tremulousness, seizures, low grade fever, and, in severe cases, delirium) may develop after abrupt discontinuation in dependent individuals.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: CNS depression is the most common finding after overdose. Respiratory depression may also occur, but is more common with coingestion of other sedative-hypnotics. Ataxia, confusion, diminished reflexes, impaired coordination, lethargy, sleepiness, and slurred speech are common with overdose. Dilated pupils may be present in overdose.
    2) SEVERE TOXICITY: Respiratory depression/arrest may occur with large overdoses. Severity of respiratory effects depends on the amount ingested and absorbed and coingestants. Atrioventricular block has been reported following overdose. In high doses, patients may manifest coma and respiratory depression. Otherwise, alprazolam is remarkably safe as a single agent.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitoring vital signs, venous blood gases, ECG, and pulse oximetry may be useful.
    B) Qualitative testing for presence of alprazolam is helpful to confirm presence, especially when overdose history is sketchy; however, quantitative levels are not usually clinically useful.
    4.1.2) SERUM/BLOOD
    A) SPECIFIC AGENT
    1) Qualitative testing for presence of alprazolam is helpful to confirm presence, especially when overdose history is sketchy. Quantitative levels are not usually clinically useful. For summary of therapeutic and toxic levels of most benzodiazepines, see (Cardoni, 1985).
    B) LABORATORY INTERFERENCE
    1) Visine(R), handsoap, Drano(R), and bleach caused false-negative tests for benzodiazepines (Mikkelsen & Ash, 1988).
    a) Urine containing benzodiazepines up to 0.78 mg/L were falsely negative with Visine at 107 mL/L.
    b) Drano or bleach at 125 mL/L interfered when drug concentrations were less than 3 mg/L.
    4.1.3) URINE
    A) Soap at concentrations of 42 mL/L interfered when drug concentrations were less than 6.5 mg/L.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor respiration, heart rate, and blood pressure.

Methods

    A) CHROMATOGRAPHY
    1) Alprazolam, 4-hydroxyalprazolam, and alpha-hydroxyalprazolam have been quantitated in serum with high performance liquid chromatography (Smith & Kroboth, 1987). The lower limit of detection was 1 ng/mL.
    B) IMMUNOASSAY
    1) SCREENING TEST: Both the ADx(R) and TDx(R) benzodiazepine test may be used for urine screening. There were some false negatives (Fraser et al, 1991).
    C) OTHER
    1) FLUMAZENIL: Flumazenil does not interfere with commonly used urine, plasma, or serum qualitative and semi-quantitative tests for benzodiazepines (EMIT-dau assay (urine), EMIT-TOX and EMIT-ST (serum/urine), benzodiazepine TDX (urine)) (Czeizel & Lendvay, 1988).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit patients with severe symptoms (ie, coma, respiratory failure, or hypotension unresponsive to IV fluids) or if a danger to themselves. Discharge when asymptomatic and when psychiatric issues have been addressed.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Healthy children with unintentional ingestions of 0.5 mg or less may be observed at home if the family is responsible. If significant ataxia or drowsiness develops, refer the patient to the hospital. Asymptomatic adults with unintentional ingestions and a good social situation may remain at home.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with intentional ingestion or significant ataxia, drowsiness, or respiratory depression should be referred to the hospital for observation. Patients with unreliable social situations may also need observation. Patients may be discharged when asymptomatic.

Monitoring

    A) Monitoring vital signs, venous blood gases, ECG, and pulse oximetry may be useful.
    B) Qualitative testing for presence of alprazolam is helpful to confirm presence, especially when overdose history is sketchy; however, quantitative levels are not usually clinically useful.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) PREHOSPITAL: Activated charcoal is usually not necessary unless the patient has a dangerous co-ingestant. Avoid if the patient is too sedated.
    B) EMESIS
    1) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression.
    C) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) AIRWAY MANAGEMENT
    1) Treat respiratory depression with assisted ventilation and/or flumazenil if available.
    B) MONITORING OF PATIENT
    1) Monitoring vital signs, venous blood gases, ECG, and pulse oximetry may be useful.
    2) Qualitative testing for presence of alprazolam is helpful to confirm presence, especially when overdose history is sketchy; however, quantitative levels are not usually clinically useful.
    C) FLUMAZENIL
    1) SUMMARY: A benzodiazepine agonist/antagonist, flumazenil, has reversed coma and respiratory depression in severely poisoned patients. Flumazenil has also been reported to reverse cardiovascular depression secondary to benzodiazepine use (Coates et al, 1991).
    2) Flumazenil is a competitive antagonist of benzodiazepines, and reverses all central effects (Prod Info ROMAZICON(R) injection, 2007; Amrein et al, 1988). It also antagonizes the depressive effect of benzodiazepine analogs like zolpidem (Wyss et al, 1996).
    3) DURATION: The duration of effect depends on the type and dose of benzodiazepine ingested, the dose of flumazenil, and the time interval between ingestion of the benzodiazepine and administration of flumazenil; it is usually 1 to 4 hours. It is also directly proportional to dosage; 3-mg doses produce the longest duration (Danton et al, 1988).
    4) Flumazenil has been shown to counteract sedation, therefore reversing the respiratory depressant effects of midazolam. Thus, use of this benzodiazepine antagonist will not cause additional respiratory depression secondary to benzodiazepine overdose (Forster et al, 1987).
    5) INDICATIONS
    a) For benzodiazepine or benzodiazepine analogs overdose and reversal of conscious benzodiazepine sedation (Prod Info ROMAZICON(R) injection, 2007).
    1) Flumazenil has been used as a diagnostic tool for comatose patients with unknown overdose ingestions. However, flumazenil should not be used if tricyclic antidepressant ingestion is suspected or if the patient has any other contraindication to flumazenil. There is no known benefit of treatment with flumazenil in a mixed drug overdose patient who is in critical condition (Prod Info ROMAZICON(R) injection, 2007; Burkhart et al, 1989; Burkhart & Kulig, 1990; Hodgkinson & Driscoll, 1991; Ahmad et al, 1991; Hojer et al, 1990; Hojer & Baehrendtz, 1988; Sprenger et al, 1994; Weinbroum et al, 1996; Winkler et al, 1993).
    2) EFFICACY: Flumazenil has been found to be effective in reducing coma in patients admitted with probable or known benzodiazepine overdoses (Ritz et al, 1990; Skielboe et al, 1991; Martens et al, 1990; O'Sullivan & Wade, 1987; Knudsen et al, 1988; Ume & Gelb, 1988; Chern et al, 1995; Proudfoot, 1995; Weinberg et al, 1994).
    6) REVERSAL OF CONSCIOUS SEDATION
    a) ADULT
    1) INTRAVENOUS: Recommended initial IV dose is 0.2 mg (2 mL), administered over 15 seconds. If adequate consciousness is not obtained within 45 seconds, a further dose of 0.2 mg (2 mL) may be repeated at 60-second intervals to a maximum total dose of 1 mg (10 mL). Most patients will respond to 0.6 to 1 mg; titrate each case as needed (Prod Info ROMAZICON(R) injection, 2007).
    a) Can be diluted in D5W, normal saline, or lactated Ringers solution. Secure the airway and have venous access prior to flumazenil administration (Prod Info ROMAZICON(R) injection, 2007).
    b) RESEDATION: In this event, repeated doses may be administered at 20-minute intervals. No more than 1 mg (given as 0.2 mg/mL) should be administered at any one time, and no more than 3 mg should be given in any one hour. In general, if a patient shows no sign of sedation within 2 hours after a 1 mg-dose of flumazenil, serious resedation at a later time is unlikely (Prod Info ROMAZICON(R) injection, 2007).
    c) CONTINUOUS INFUSION: The use of continuous flumazenil maintenance infusion over 5 to 24 hours seems of therapeutic value in the event of resedation after initial response (Winkler et al, 1993; Weinbroum et al, 1996; Brammer et al, 1998).
    1) CASE REPORT: Continuous intravenous flumazenil infusion was initiated, at a rate of 1.0 mg/hour, in a 24-year-old female who presented with coma (Glasgow Coma score of 8) and clinical hypoventilation after an overdose ingestion of flunitrazepam tablets (total dose of 100 mg). Prior to initiation of the infusion, the patient had received several intravenous boluses of flumazenil which increased her Glasgow Coma score to 15 with normalization of ventilation. After initiation of the infusion, the patient continually maintained a Glasgow Coma score of 15. Discontinuation of the flumazenil infusion, fourteen hours later, resulted in resedation and hypoventilation of the patient. The infusion was restarted at 1 mg/hr and, 30 hours later, was discontinued without recurrence of resedation or hypoventilation (Brammer et al, 2000).
    2) CASE REPORT: Continuous infusion of flumazenil 0.5 to 1 mg/hr was used to treat a patient with CNS depression attributed to accumulation of chlordiazepoxide and its active metabolites (Maxa et al, 2003).
    3) EXPERIMENTAL ROUTE OF ADMINISTRATION: A study was conducted to determine if therapeutic plasma concentrations of flumazenil can be achieved with endotracheal administration. Six elective surgical patients received 1 mg flumazenil in 10 mL of saline intratracheally during general anesthesia. Therapeutic blood levels of flumazenil were attained within 1 minute after flumazenil administration and there were no adverse effects reported among the 6 patients (Palmer et al, 1998).
    b) PEDIATRIC
    1) For reversal of the sedative effects of benzodiazepines after conscious sedation, the usual dose of flumazenil in children 1 year or older is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds. If adequate anesthesia reversal does not occur after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) may be repeated at 1-minute intervals as needed, up to 4 times. The maximum total dose is 0.05 mg/kg or 1 mg, whichever is lower (Prod Info ROMAZICON(R) injection, 2007).
    a) The safety and efficacy of flumazenil have not been established in pediatric patients less than one year of age for reversal of sedative effects of benzodiazepines after conscious sedation (Prod Info ROMAZICON(R) injection, 2007).
    b) RESEDATION: The safety and efficacy of administering repeated doses of flumazenil in pediatric patients in the case of resedation have not been established (Prod Info ROMAZICON(R) injection, 2007).
    c) In a study conducted to determine the safety and efficacy of flumazenil for the reversal of benzodiazepine-induced conscious sedation in children, flumazenil was given in incremental doses of 0.01 mg/kg (0.2-mg maximum dose) at 1-minute intervals, to a maximum total dose of 0.05 mg/kg (1-mg maximum dose).
    1) One hundred out of 107 children (96%) who received flumazenil partially or completely responded to the flumazenil by 10 minutes after administration. The most frequently occurring adverse effects included abnormal crying, agitation, and aggressiveness which were possibly related to flumazenil administration (Shannon et al, 1997).
    7) TREATMENT OF BENZODIAZEPINE OVERDOSE
    a) ADULT
    1) Recommended initial intravenous dose is 0.2 mg (2 mL), administered over 30 seconds. If adequate consciousness is not obtained within 30 seconds, a further dose of 0.3 mg (3 mL) may be administered over 30 seconds (Prod Info ROMAZICON(R) injection, 2007).
    2) Further doses of 0.5 mg (5 mL) may be administered at 1 minute intervals up to a maximum total dose of 3 mg (30 mL). Most patients will respond to 1 to 3 mg; doses beyond 3 mg do not usually produce additional effects (Prod Info ROMAZICON(R) injection, 2007).
    3) Occasionally, patients with partial response at 3 mg may require a 5-mg total dose for full response. If a patient has not responded within 5 minutes of administration of a 5-mg total dose, the major cause of sedation is not likely to be benzodiazepines (Prod Info ROMAZICON(R) injection, 2007).
    4) Many clinicians have found that higher doses, 1 to 10 mg in an adult, may be necessary to treat the profound coma in some overdose cases (Lheureux & Askenasi, 1988; Personal Communication, 1992; Mapelli et al, 1988; Prischl et al, 1988; Rouzioux et al, 1988).
    b) PEDIATRIC
    1) Administer an initial dose of 0.01 mg/kg (up to 0.2 mg) in children 1-year-old or older; repeat as necessary at 60-second intervals, up to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is less (Prod Info ROMAZICON(R) injection, 2007).
    2) Flumazenil has also been used in children, 4, 7, and 13 years of age, who overdosed on benzodiazepines in doses of 10 mcg/kg intravenously for 2 doses (Wood et al, 1988) and in a 3-year-old girl following an overdose ingestion of lorazepam (total amount ingested was approximately 15 mg) (Clark et al, 1995).
    3) NEONATES: Flumazenil administration consisted of 0.02 mg/kg intravenous loading dose followed by 0.05-mg/kg/hour maintenance infusion of 6 hours duration in a neonate following maternal benzodiazepine ingestion (Richard et al, 1991).
    a) A woman received 20 mg of diazepam intravenously 1 hour prior to the caesarean section delivery of an apneic, blue, hypotonic male infant. The infant received flumazenil 10 mcg/kg intravenously with vigorous movement and respiratory effort following in 1 minute. A flumazenil infusion of 10 mcg/kg/hour was continued for 6 hours with no further episodes of apnea or desaturation. An uneventful recovery ensued (Cone et al, 1993).
    4) FETAL: Administration of flumazenil (0.3 mg), to a 22-year-old primipara (36 weeks gestation) who overdosed on diazepam, restored the normal beat-to-beat variation and periodic oscillations of amplitude of fetal heart rate. No adverse effects or withdrawal symptoms were reported (Stahl et al, 1993).
    8) CONTRAINDICATIONS
    a) Flumazenil should not be used in patients with serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, seizure), dysrhythmias (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), or cardiovascular collapse at presentation. Flumazenil should not be used until the effects of neuromuscular blocking agents have worn off (Prod Info ROMAZICON(R) injection, 2007).
    b) Flumazenil should not be used in patients who are benzodiazepine-dependent or who have been given benzodiazepines for control of a life-threatening condition (Prod Info ROMAZICON(R) injection, 2007).
    1) In a small, 10-week study of benzodiazepine overdose patients (n=22) who presented to an emergency department, 21 of the patients were NOT eligible to receive flumazenil due to daily benzodiazepine use (Thomson et al, 2006).
    c) There is no known benefit of treatment with flumazenil in a mixed drug overdose patient who is in critical condition. Flumazenil should NOT be used in cases where seizures are likely, from any cause (Prod Info ROMAZICON(R) injection, 2007).
    1) Precipitation of seizures may occur in epileptic patients or those coingesting epileptogenic agents (Bismuth et al, 1985). Seizure has also been reported after flumazenil administration in a pediatric patient (McDuffee & Tobias, 1995).
    d) TRICYCLIC ANTIDEPRESSANTS: Flumazenil is NOT recommended for use when patients show signs of tricyclic antidepressant toxicity; the patient should be allowed to remain sedated (with respiratory and other support) until the tricyclic signs abate. Concurrent ingestion of large doses of tricyclic antidepressants may predispose patients to seizures upon flumazenil administration (Prod Info ROMAZICON(R) injection, 2007).
    1) Deaths have occurred after flumazenil treatment in mixed overdose patients who have ingested large doses of tricyclic antidepressants.
    2) CASE REPORT: A 42-year-old female who ingested 80 mg of clonazepam and 1 g of imipramine, had a generalized tonic-clonic seizure 5 minutes after receiving 1 mg of flumazenil (0.25 mg/minute). The seizure stopped during injection of 10 mg of diazepam and did not recur (Mordel et al, 1992).
    3) ANIMAL DATA: Flumazenil 5 mg/kg did not cause seizures in mice overdosed with diazepam and either imipramine or maprotiline. Flumazenil also did not cause acute withdrawal from large doses of diazepam (Geller et al, 1991).
    4) ANIMAL DATA: Flumazenil 0.2 mg/kg was given to 6 dogs overdosed on amitriptyline and midazolam. Four of six dogs developed seizures within 4 minutes. The author suggested that seizures were not reported in other animal studies due to the slight anticonvulsant effect of the higher doses of flumazenil (5 mg/kg) used in those studies (Lheureux et al, 1992).
    e) In one controversial study, flumazenil reversed alcoholic overdose coma within 60 minutes in contrast to 15 minutes for pure benzodiazepine only ingestions (Brogden & Goa, 1988).
    1) Flumazenil is generally not recommended or used for alcohol overdose, being reserved for benzodiazepines.
    9) ADVERSE EFFECTS
    a) Adverse effects have included fatigue, nausea and vomiting, agitation, confusion, and rarely seizures and cardiac arrhythmias. Heart block has been reported in one elderly patient given flumazenil following possible benzodiazepine and acetaminophen overdose (Herd & Clarke, 1991). Panic attacks may occur in patients under psychiatric care; signs associated with head trauma may be exacerbated in some patients.
    1) Be prepared to treat any of these signs; most seizures have responded to treatment with benzodiazepines, phenytoin, or barbiturates.
    2) Deaths have occurred in patients treated with flumazenil; most of these occurred with severe underlying disease states or overdoses of large amounts of non-benzodiazepines (Bodenham, 1989; Lim, 1989).
    3) In clinical studies, most adverse reactions were an extension of the pharmacologic effects of flumazenil in reversing benzodiazepine effects (Prod Info ROMAZICON(R) injection, 2007).
    4) WITHDRAWAL: Withdrawal syndromes have been reported after single overdoses of benzodiazepines (Lopez & Rebollo, 1990); be prepared to treat for this possibility (signs may include seizures).
    5) FLUMAZENIL OVERDOSE: Large intravenous doses of flumazenil administered to healthy volunteers with no benzodiazepine on board did not cause any serious adverse effects. Animal toxicology studies reveal that the risk in man given therapeutic doses or even accidental/intentional overdoses is extremely small. The agent has a wide margin of safety (Schlappi et al, 1988).
    10) SAFETY
    a) CLINICAL TRIALS
    1) Use of flumazenil to reverse midazolam-induced sedation in subjects who had taken diazepam or triazolam was effective and caused no significant changes in laboratory values, vital signs, or EKG (Danton et al, 1988).
    b) In a double-blind study including 18 patients in whom a benzodiazepine intoxication was suspected, flumazenil (Lanexat(R), RO-15,4513) was compared with placebo. There was a highly significant effect on consciousness; all patients awakened, usually within minutes. No adverse effects were observed. In 2 patients, the clinical condition deteriorated 1 to 2 hours after the antagonist was given (Aarseth et al, 1988).
    c) A two-phase study (a controlled, randomized, double-blind study followed by a prospective, open study) was performed. Unconscious patients (n=110) suspected of benzodiazepine overdose were treated with flumazenil. The first 31 patients were studied in a double-blind fashion while the others were studied according to an open protocol. Patients who remained unconscious among the double-blind patients and those who relapsed into coma after the first dose of flumazenil were later treated in the open phase portion of the study.
    1) Fourteen of 17 double-blind patients regained consciousness after an average administration of flumazenil 8 mg compared with 1 of 14 placebo patients (p less than 0.001). Twenty-five percent of patients did not regain consciousness due to ingestions of high concentrations of non-benzodiazepine drugs. Sixty percent of the responders remained awake for 72 +/- 37 minutes. Forty percent relapsed into coma after 18 +/- 7 minutes and various CNS depressant drugs were detected in their blood in addition to benzodiazepines.
    2) Flumazenil adverse effects included 5 cases of transient hypertension and tachycardia and 27 cases of mild anxiety, restlessness, and aggression (Weinbroum et al, 1996)
    d) A prospective study was conducted to determine the cardiovascular response and stress reaction following flumazenil administration to patients sedated with a midazolam infusion. The patients' level of consciousness increased significantly after administration of flumazenil and returned to baseline within 30 minutes. The patients did not experience any significant stress reactions to the flumazenil; however, there were transient elevations in heart rate, blood pressure, systolic pulmonary artery pressure, and pulmonary artery occlusion pressure (Kamijo et al, 2000).
    D) ATRIOVENTRICULAR BLOCK
    1) Mullins (1999) reported that a 28-year-old male developed first degree AV block and drowsiness following 12 milligrams of alprazolam. The patient was given a titrated dose of flumazenil and an immediate shortening of the PR interval was observed along with improved neurological function. Symptoms reappeared approximately 40 minutes later, and the patient again responded to flumazenil therapy. The patient was discharged without sequelae 2.5 hours after his last dose (Mullins, 1999).
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    F) DRUG WITHDRAWAL
    1) PHENOBARBITAL
    a) Initial management should be administration of phenobarbital as a replacement for alprazolam (Ravi et al, 1990).
    b) Thirty milligrams of phenobarbital is equivalent to 0.5 milligram of alprazolam. One fourth of this calculated dose should be administered and increased as necessary to relieve abstinence symptoms.
    c) A gradual taper of phenobarbital can be instituted as soon as the patient has become stable for 48 hours. Taper at a rate of 10 percent/day.
    2) BENZODIAZEPINES
    a) Alternatively, the benzodiazepines may be administered and then tapered by 10 percent/day for 10 days.
    b) Relative potency of the benzodiazepine being withdrawn from should be considered when estimating the appropriate dose of the benzodiazepine chosen for treatment of withdrawal (Schneider et al, 1987; Albeck, 1987).
    c) CHLORDIAZEPOXIDE: Twenty-five milligrams of chlordiazepoxide is equivalent to 0.5 milligram of alprazolam.
    d) CLONAZEPAM: Patterson (1988, 1990) reported successful withdrawal from alprazolam over a seven-day period using a clonazepam substitution regimen (Patterson, 1990).
    e) DIAZEPAM
    1) Harrison et al (1984) managed benzodiazepine withdrawal by giving one-half of the reported daily dose in diazepam, decreasing the dose by approximately 10 percent each day (Harrison et al, 1984).
    2) Five milligrams of diazepam is equivalent to 0.5 milligram of alprazolam.
    f) LORAZEPAM: Acute manic-like behavior (Lapierre & Labelle, 1987) and psychosis and delirium (Heritch et al, 1987) have been reported after abrupt withdrawal of lorazepam.
    3) BUSPIRONE: May be an effective treatment of anxiety in alprazolam-dependent patients (Kranzler, 1989).
    a) The Hamilton Anxiety rating Scale score worsened when the dosage of buspirone was reduced and the score improved when the higher dosage was resumed in a 34-year-old male being treated for alprazolam and alcohol dependence (Kranzler, 1989).
    4) PROPRANOLOL: 20 milligrams three to four times daily starting on the 5th day and continued for 2 weeks has been shown to be of use in benzodiazepine withdrawal (Smith & Wesson, 1983; Wilbur & Kulik, 1983).
    5) CARBAMAZEPINE
    a) Carbamazepine has been used for the treatment of alprazolam withdrawal (Klein et al, 1986).
    b) Lawlor (1987) suggests that carbamazepine may act to suppress reemergent panic symptoms rather than alleviate the symptoms of alprazolam withdrawal (Lawlor, 1987).
    c) Additional studies are needed to demonstrate the efficacy of carbamazepine treatment of alprazolam withdrawal.
    G) CONTRAINDICATED TREATMENT
    1) Stimulants are contraindicated in treatment of benzodiazepine poisonings.
    H) PHYSOSTIGMINE
    1) Physostigmine was not clinically effective in one report (Pandit et al, 1981), and its use is not recommended.
    2) Benzodiazepines may have central anticholinergic activity indirectly mediated through facilitation of the GABA system, which physostigmine may antagonize (Rupreht, 1980).

Enhanced Elimination

    A) DIURESIS/HEMODIALYSIS
    1) Forced diuresis or hemodialysis are ineffective.

Abstracts

Case Reports

    A) ADULT
    1) A case of delirium during withdrawal of alprazolam occurred in a 68-year-old male that was unresponsive to diazepam administration (40 mg over 14 hours). Delirium resolved after reinstitution of alprazolam (Zipursky et al, 1985).
    2) A case of alprazolam-induced manic reaction in a 54-year-old female patient being treated for agoraphobia and panic disorder was reported. Mania was controlled with low-dose lithium carbonate (Mayerhoff et al, 1986)

Range Of Toxicity

Summary

    A) TOXICITY: Deaths from benzodiazepine overdose are extremely rare. A patient with multiple severe medical problems expired following an overdose of 7.5 mg of alprazolam. In general, the toxic-to-therapeutic ratio is very high for benzodiazepines, making them remarkably safe medications.
    B) Ataxia, sleepiness, and slurred speech may be noted following ingestion of the first therapeutic dose of these agents, especially in children.
    C) THERAPEUTIC DOSE: ADULTS: As an anti-anxiety agent, the recommended dose is 0.25 to 0.5 mg given orally three times a day up to a maximum daily dose of 4 mg. For the treatment of panic disorder, the usual recommended dose ranges from 3 to 6 mg daily.

Therapeutic Dose

    7.2.1) ADULT
    A) DISEASE STATE
    1) GENERALIZED ANXIETY DISORDER
    a) The recommended initial dose is 0.25 to 0.5 mg ORALLY 3 times daily. Dose increases may done in 3 to 4 day intervals to MAXIMUM of 4 mg/day (in divided doses) (Prod Info XANAX(R) oral tablets, 2011; Prod Info NIRAVAM(R) orally disintegrating tablets, 2011; Prod Info ALPRAZOLAM INTENSOL(TM) oral solution, 2007).
    2) PANIC DISORDER
    a) The recommended initial dose is 0.5 mg ORALLY 3 times daily. Dose increase may done in increments no greater than 1 mg/ day and in intervals of 3 to 4 days (Prod Info XANAX(R) oral tablets, 2011; Prod Info NIRAVAM(R) orally disintegrating tablets, 2011; Prod Info ALPRAZOLAM INTENSOL(TM) oral solution, 2007).
    b) ORAL EXTENDED-RELEASE TABLETS: Initially, 0.5 to 1 mg once daily. Dose increase may done in increments no greater than 1 mg/ day and in intervals of 3 to 4 days. The usual recommended dose ranges from 3 to 6 mg/day. Some patients may require doses greater than 6 mg/day (Prod Info XANAX(R) XR oral extended-release tablets, 2011).
    7.2.2) PEDIATRIC
    A) Safety and efficacy have not been established in pediatric patients (Prod Info XANAX(R) oral tablets, 2011; Prod Info NIRAVAM(R) orally disintegrating tablets, 2011; Prod Info XANAX(R) XR oral extended-release tablets, 2011).

Minimum Lethal Exposure

    A) A patient with multiple severe medical problems expired following an overdose of 30 tablets of 0.25 milligram alprazolam (Litovitz, 1987).

Maximum Tolerated Exposure

    A) Ingestion of 20 to 60 milligrams of alprazolam produced sedation in a 45-year-old female and combativeness in a 29-year-old female (McCormick et al, 1985).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Alprazolam plasma levels of 350 nanograms/mL have produced mild symptoms (McCormick et al, 1985).
    2) DOSE/SEDATION CORRELATION: Degree of impairment and sedation related better to dose than blood concentration in a study of 3 different doses (0.25 mg every 8 hours, 0.5 mg every 8 hours, and 2 mg every 12 hours) in elderly patients (Kroboth et al, 1990).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)RAT:
    1) 331 to 2171 mg/kg (Prod Info alprazolam oral tablets, 2007)

Physicochemical

Physical Characteristics

    A) Alprazolam is a white (Prod Info ALPRAZOLAM oral disintegrating tablets, 2010; Prod Info alprazolam oral extended-release tablets, 2009) to off white crystalline powder that is soluble in methanol or ethanol, but has no appreciable solubility in water at physiological pH (Prod Info ALPRAZOLAM INTENSOL(TM) oral solution, 2007; Prod Info alprazolam oral tablets, 2007).

Molecular Weight

    A) 308.76 (Prod Info ALPRAZOLAM oral disintegrating tablets, 2010; Prod Info alprazolam oral extended-release tablets, 2009)

References

General Bibliography

    1) AMADE: AMA Drug Evaluations, 5th ed, American Medical Association, Chicago, IL, 1983, pp 183.
    2) Aarseth HP, Bredesen JE, & Grynne B: Benzodiazepine-receptor antagonist, a clinical double-blind study. Clin Toxicol 1988; 26:283-292.
    3) Abernethy D, Greenblatt DJ, & Divoll M: The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokin 1984; 9:177-183.
    4) Ahmad Z, Herepath M, & Ebden P: Diagnostic utility of flumazenil in coma with suspected poisoning (letter). BMJ 1991; 302(6771):292.
    5) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
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